Asymmetric synthesis of a stereopentade fragment toward latrunculins

Latrunculins are marine toxins used in cell biology to block actin polymerization. The development of new synthetic strategies and methods for their synthesis is thus important in order to improve, modulate or control this biological value. The total syntheses found in the literature all target similar disconnections, especially an aldol strategy involving a recurrent 4-acetyl-1,3-thiazolidin-2-one ketone partner. Herein, we describe an alternative disconnection and subsequent stereoselective transformations to construct a stereopentade amenable to latrunculin and analogue synthesis, starting from (+)-β-citronellene. Key stereoselective transformations involve an asymmetric Krische allylation, an aldol reaction under 1,5-anti stereocontrol, and a Tishchenko–Evans reduction accompanied by a peculiar ester transposition, allowing to install key stereogenic centers of the natural products.


General information
All reactions were performed in flame-dried flasks fitted with rubber septa under a positive pressure of argon. DCM and Et2O were purified using a MB-SPS 800 (MBraun Solvent Purification System). THF was distilled over sodium and benzophenone.
Anhydrous DMF was purchased from Merck. Other solvents were purchased from suppliers and were of technical quality. Petroleum ether refers to the fraction of petroleum boiling between 40 and 60 °C. Reagents were purchased and used without further purification except for allyl acetate and DiPEA, which were distilled.
Analytical TLC were carried out on aluminum plates coated with Merck F254 silica gel 60 and visualized by exposure to 240 nm UV light and/or exposure to a basic solution of potassium permanganate followed by heating. Column flash chromatography was performed using Merck PLC silica gel 60.

Compound preparation and characterization (S)-4-Methylhex-5-en-1-ol (11)
A three-necked round bottom flask was charged with dry CH2Cl2 (60 mL) and (+)-βcitronellene (10, 1.3 mL, 7.14 mmol, 1 equiv). The solution was cooled down to −78 °C and a stream of ozone was bubbled for 55 min. The reaction was followed by TCL until near full consumption of the starting material. Without waiting for the full disappearence of 10 to avoid over-oxidation of the second double bond, NaBH4 was added (570 mg, 21.4 mmol, 3.0 equiv) followed EtOH (5 mL). The reaction was left at room temperature for 3 h 30. The reaction was carefully quenched with a 1 M solution of HCl, the product was extracted with DCM (2 × 50 mL), washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (pentane/Et2O: 80/20) yielded product 11 as a transparent oil (638 mg, 78% yield).
Characterization data were in accordance with those of the literature [1,2].

NMR analysis of Mosher esters of alcohol 12
Mosher esters S1 and S2 were prepared from 12 following the following procedure: A round bottom flask was charged with 50 mg of (R)-or (S)-α-methoxy-αtrifluoromethylphenylacetic acid (MTPA, or Mosher's acid) (0.21 mmol, 1 equiv), 10 mL S5 of n-hexane and 16 µL of DMF (0.21 mmol, 1.0 equiv). To this solution was added 85 µL of (COCl)2 (1.0 mmol, 4.7 equiv) and the reaction was stirred at room temperature for 1 hour. The opaque solution was filtered and evaporated under argon flow. The crude acyl chlorides were used as such in the next step: A round bottom flask was charged with 5 mg (0.03 mmol, 1 equiv) of 12, 0.1 mL of dry CH2Cl2, 1 mg of DMAP (0.008 mmol, 20% equiv) and 10 µL of NEt3 (0.07 mmol, 2.2 equiv). The solution was placed at 0 °C and 0.5 mL of a 0.1 M solution of the acyl chloride (0.05 mmol, 1.4 equiv) in CH2Cl2 was added. The reaction was kept at 0 °C for 1 hour then left at room temperature for another 2 h. The solution was concentrated under reduced pressure and the product isolated by column chromatography (pentane/Et2O: 90/10). The two compounds were analyzed by 1 H NMR and the chemical shifts of the two esters were compared [3]. The protons of the C5-C9 chain on the carbinol ester were found more shielded (upfield-shifted) with the (R)-MTPA ester S1 than with the (S)-MTPA ester S2 (Table S1), showing an anisotropic effect of the phenyl group on the same side. Conversely, the protons of the C1-C3 substituent were found less shielded.
This observation indicates an (R)-configuration at C4. A copy of NMR spectra is shown in Figure 1.